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Main unadjusted effects of smoking, childhood and adult exposure to tobacco smoke and lung cancer risk.

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.

Characteristics of cases and controls from three studies combined.

Association between rs4809294 and rs2292975 and lung cancer risk stratified by exposure to secondhand smoke during adulthood in the NCI-MD Cohort (European Americans).

Association between 3'UTR SNPs and lung cancer in the NCI-MD Cohort (European Americans).

NCI-MD Case-Control Study Genomic DNA was isolated from buffy coat samples containing white blood cells using Flexigene DNA Kit (Qiagen) according to the manufacturer's instructions.

Flowchart detailing the selection process of SNPs. Rs686 in DRD1 was selected from the literature as being a miRNA-binding modulating SNP (Huang and Li, 2009 Biol Pschiatry, 65 9 702-705).

Test for departure from additivity for rs686 and exposure to secondhand smoke during childhood.

Association between rs686 and lung cancer risk stratified by exposure to secondhand smoke during adulthood.

Relationship between rs686 and pack-years of smoking (A) in the NCI-MD (B) and Wayne State (C) studies. Relationship between rs686 and age at smoking initiation (D) in the NCI-MD study.

SNP Selection.

Supplementary Table S1. Concordance between blinded, randomized duplicates and average serum cytokine limits of detection

PDF file - 67K, Imputed SNP associations from the case-control analysis of lung cancer (by histology) in African-Americans (P

Tables S1-S6 and Figures S1-S3.

PDF file - 561K, Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for missense variant rs16969968. Black circles depict association of SNPs with lung cancer, adjusted for sex, age, study site, % African ancestry, % European ancestry, and number of pack-years smoked. Open squares depict association of SNPs with lung cancer, adjusted for sex, age, study site, and % African ancestry, % European ancestry, number of pack-years smoked, AND conditioned on rs16969968 (marked with an X).

Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans.Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate.Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5).Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma.Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.

Background: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk.Methods: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than −950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than −856 HU on expiratory scan (HUE).Results: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels E as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03–1.06] and FEV1/FVC < 0.70 (OR = 1.71; 95% CI, 1.21–2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD.Conclusion: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer.Impact: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341–7. ©2016 AACR.

SUPPLEMENTAL TABLE 1. Summary of the five previously reported lung cancer survival GWAS variants examined in the present study. SUPPLEMENTAL TABLE 2. Descriptive characteristics of African Americans with NSCLC participating in the KCI/WSU and UCSF studies. SUPPLEMENTAL TABLE 3. Allele frequency for the five variants previously associated with lung cancer survival in the NHGRIEBI GWAS Catalog in the SCCS (N=275), KCI/WSU (N=312), and UCSF (N=284) populations. Allele frequencies are also presented for the ASW 1000 Genomes African American reference population and for the 1000 Genomes reference population that matches the racial/ethnic group of the original discovery population (CEU or CHB). SUPPLEMENTAL TABLE 4. Adjusted multivariable Cox proportional hazards model results for African Americans with incident non-small cell lung cancer participating in the Southern Community Cohort Study (N=264) for the five candidate SNPs previously associated with lung cancer survival from the NHGRI GWAS catalog. SUPPLEMENTAL TABLE 5. Stage-stratified multivariable Cox proportional hazards results for the association of rs1878022 and overall survival in the SCCS and pooled KCI/WSU and UCSF populations. SUPPLEMENTAL TABLE 6. Allele frequency for common variants associated survival in the SCCS (N=275), KCI/WSU (N=312), and UCSF (N=284) populations. Allele frequencies are also presented for the ASW 1000 Genomes African American reference population. SUPPLEMENTAL TABLE 7. Adjusted multivariable Cox proportional hazards results for African Americans with incident non-small cell lung cancer participating in the Southern Community Cohort Study (N=264) for common variants assayed by the Illumina HumanExome BeadChip v1.1. SUPPLEMENTAL FIGURE 1. Flow chart of quality control (QC) for the SCCS genotyping data. SUPPLEMENTAL FIGURE 2. Distribution of stage at diagnosis across the SCCS (N=286), KCI/WSU (N=316), and UCSF (N=298.) SUPPLEMENTAL FIGURE 3. Global genetic ancestry estimates for African Americans with NSCLC participating in the (A) SCCS, (B) KCI/WSU, and (C) UCSF study populations.SUPPLEMENTAL FIGURE 4. Linkage disequilibrium (LD) patterns +/-10kb surrounding the CMKLR1 gene region in the YRI and CEU populations (A and B, respectively) from 1000 Genomes (phase 3). LD patterns surrounding rs1878022 (denoted by black arrow) are presented as inserts. 1000 Genomes data and Haploview software were utilized to display r2 values (filters:Hardy-Weinberg p-value > 0.001, genotyping efficiency > 90%, and minor allele frequency >0.05).SUPPLEMENTAL FIGURE 5. H3K4me1 and H3K27Ac histone modification marks surrounding rs1878022 in the CMKLR1 gene, visualized using the UCSC Genome Browser. Marks in (A) are specific to normal human lung fibroblast (NHLF) cell lines from the ENCODE project. Marks in (B) are for all cell lines (GM12878, H1-hESC, HSMM, HUVEC, K562, NHEK, and NHLF) in the ENCODE project.

PDF file - 559K, Association of SNPs on chromosome 15q25.1 with lung cancer, with and without adjustment for pack-years smoked. Black circles depict association of SNPs with lung cancer, adjusted for sex, age, study site, % African ancestry, % European ancestry, and number of pack-years smoked. Open squares depict association of SNPs with lung cancer, adjusted for sex, age, study site, and % African ancestry, % European ancestry, but NOT number of pack-years smoked.

Purpose:Identifying novel driver genes and mutations in African American non–small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population.Experimental Design:Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations.Results:Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic.Conclusions:These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

Agreement (Cohen's kappa) between measures of COPD among lung cancer cases (upper diagonal) and controls (lower diagonal).

PDF file - 926K, Triangle plot showing estimated admixture in the African-American case-control population. Estimates were performed using 102 AIMs and data from the International HapMap Project on 167 Yoruban African (Green dots), 165 European (Red dots), 84 Chinese (Yellow dots) and 86 Japanese (Dark Blue dots) founders. The figure depicts ancestry in 1308 African-American lung cancer cases (Pink dots) and 1241 controls (Light Blue dots).

Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases.Methods: Incident non–small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication.Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54–0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71–0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33–0.66).Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene–environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival.Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288–95. ©2017 AACR.

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Genome-wide association studies (GWAS) have identified several loci contributing to lung cancer and COPD risk independently; however, inflammation-related pathways likely harbor additional lung cancer risk-associated variants in biologically relevant immune genes that differ dependent on COPD. We selected single nucleotide polymorphisms (SNPs) proximal to 2,069 genes within 48 immune pathways. We modeled the contribution of these variants to lung cancer risk in a discovery sample of 1,932 lung cancer cases and controls stratified by COPD status and validation sample of 953 cases and controls also stratified by COPD. There were 43 validated SNPs in those with COPD and 60 SNPs in those without COPD associated with lung cancer risk. Furthermore, 29 of 43 and 28 of 60 SNPs demonstrated a statistically significant interaction with COPD in the pooled sample. These variants demonstrated tissue-dependent effects on proximal gene expression, enhanced network connectivity and resided together in specific immune pathways. These results reveal that key inflammatory related genes and pathways, not found in prior GWAS, impact lung cancer risk in a COPD-dependent manner. Genetic variation identified in our study supplements prior lung cancer GWAS and serves as a foundation to further interrogate risk relationships in smoking and COPD populations.

Background Coronavirus disease 2019 (COVID‐19) has had profound effects on population health to date. African American cancer survivors are particularly vulnerable to developing severe consequences; therefore, understanding the impact of the virus on this patient population is critical. Methods The Detroit Research on Cancer Survivors cohort is a unique effort to understand the determinants of poor outcomes in African American cancer survivors. To date, more than 4500 cancer survivors and nearly 950 primary caregivers have been enrolled; participation includes a survey and the collection of biospecimens, medical records, and tumor tissue. Beginning in the spring of 2020, a supplemental survey focusing on the impact of COVID‐19 was offered to enrolled participants. The analysis included 890 survivors. Results Nearly all survivors (>99%) reported changes in their daily activities in an effort to reduce the risk of infection. More than 40% of the survivors reported some disruption in their access to medical care. A substantial proportion of the survivors (>40%) reported feeling anxious, depressed, and/or isolated during the COVID‐19 pandemic. Approximately 40% of the patients reported changes in health behaviors shown to negatively affect survivorship outcomes (physical inactivity, smoking, and alcohol use) as a result of the pandemic. Conclusions The influence of the COVID‐19 pandemic on African American cancer survivors is substantial: it has affected both their physical and mental health. Coupled with changes in health behaviors, these factors will likely affect outcomes in this high‐risk patient population, and this makes further study and interventions necessary to mitigate the long‐term impact of the pandemic on cancer outcomes., The COVID‐19 pandemic has had a profound impact on the physical and mental health of African American cancer survivors living in Detroit, Michigan. Strategies focusing on health behaviors such as physical activity would improve patient health and quality of life.

Background: Somatic EGFR mutations define a subset of non–small cell lung cancers (NSCLC) that have clinical impact on NSCLC risk and outcome. However, EGFR-mutation-status is often missing in epidemiologic datasets. We developed and tested pragmatic approaches to account for EGFR-mutation-status based on variables commonly included in epidemiologic datasets and evaluated the clinical utility of these approaches. Methods: Through analysis of the International Lung Cancer Consortium (ILCCO) epidemiologic datasets, we developed a regression model for EGFR-status; we then applied a clinical-restriction approach using the optimal cut-point, and a second epidemiologic, multiple imputation approach to ILCCO survival analyses that did and did not account for EGFR-status. Results: Of 35,356 ILCCO patients with NSCLC, EGFR-mutation-status was available in 4,231 patients. A model regressing known EGFR-mutation-status on clinical and demographic variables achieved a concordance index of 0.75 (95% CI, 0.74–0.77) in the training and 0.77 (95% CI, 0.74–0.79) in the testing dataset. At an optimal cut-point of probability-score = 0.335, sensitivity = 69% and specificity = 72.5% for determining EGFR-wildtype status. In both restriction-based and imputation-based regression analyses of the individual roles of BMI on overall survival of patients with NSCLC, similar results were observed between overall and EGFR-mutation-negative cohort analyses of patients of all ancestries. However, our approach identified some differences: EGFR-mutated Asian patients did not incur a survival benefit from being obese, as observed in EGFR-wildtype Asian patients. Conclusions: We introduce a pragmatic method to evaluate the potential impact of EGFR-status on epidemiological analyses of NSCLC. Impact: The proposed method is generalizable in the common occurrence in which EGFR-status data are missing.

PURPOSE: Computed tomography (CT) is an effective method for detecting and characterizing lung nodules in vivo. With the growing use of chest CT, the detection frequency of lung nodules is increasing. Noninvasive methods to distinguish malignant from benign nodules have the potential to decrease the clinical burden, risk, and cost involved in follow-up procedures on the large number of false-positive lesions detected. This study examined the benefit of including perinodular parenchymal features in machine learning (ML) tools for pulmonary nodule assessment. METHODS: Lung nodule cases with pathology confirmed diagnosis (74 malignant, 289 benign) were used to extract quantitative imaging characteristics from computed tomography scans of the nodule and perinodular parenchyma tissue. A ML tool development pipeline was employed using k-medoids clustering and information theory to determine efficient predictor sets for different amounts of parenchyma inclusion and build an artificial neural network classifier. The resulting ML tool was validated using an independent cohort (50 malignant, 50 benign). RESULTS: The inclusion of parenchymal imaging features improved the performance of the ML tool over exclusively nodular features (P < 0.01). The best performing ML tool included features derived from nodule diameter-based surrounding parenchyma tissue quartile bands. We demonstrate similar high-performance values on the independent validation cohort (AUC-ROC = 0.965). A comparison using the independent validation cohort with the Fleischner pulmonary nodule follow-up guidelines demonstrated a theoretical reduction in recommended follow-up imaging and procedures. CONCLUSIONS: Radiomic features extracted from the parenchyma surrounding lung nodules contain valid signals with spatial relevance for the task of lung cancer risk classification. Through standardization of feature extraction regions from the parenchyma, ML tool validation performance of 100% sensitivity and 96% specificity was achieved.

INTRODUCTION: The relationship between Body-Mass-Index (BMI) and lung cancer prognosis is heterogeneous. We evaluated the impact of sex, smoking and race on the relationship between BMI and overall survival (OS) in non-small-cell-lung-cancer (NSCLC). METHODS: Data from 16 individual ILCCO studies were pooled to assess interactions between BMI and the following factors on OS: self-reported race, smoking status and sex, using Cox models (adjusted hazard ratios; aHR) with interaction terms and adjusted penalized smoothing spline plots in stratified analyses. RESULTS: Among 20,937 NSCLC patients with BMI values, females = 47 %; never-smokers = 14 %; White-patients = 76 %. BMI showed differential survival according to race whereby compared to normal-BMI patients, being underweight was associated with poor survival among white patients (OS, aHR = 1.66) but not among black patients (aHR = 1.06; p(interaction) = 0.02). Comparing overweight/obese to normal weight patients, Black NSCLC patients who were overweight/obese also had relatively better OS (p(interaction) = 0.06) when compared to White-patients. BMI was least associated with survival in Asian-patients and never-smokers. The outcomes of female ever-smokers at the extremes of BMI were associated with worse outcomes in both the underweight (p(interaction)

BACKGROUND: Family history (FH) remains one of the strongest risk factors for many common cancers and is used to determine cancer genetic counseling (CGC) eligibility, but the understanding of familial cancer patterns in African Americans is limited. METHODS: This study evaluated cancer FH among African Americans with invasive breast cancer, prostate cancer, lung cancer, or colorectal cancer (CRC) in the Detroit Research on Cancer Survivors (ROCS) cohort. Associations between participant cancer type, site-specific FH, and meeting national guidelines for CGC were evaluated via logistic regression. Cancer FH patterns were evaluating via hierarchical clustering. RESULTS: Among 1500 ROCS participants, 71% reported at least 1 first-degree relative or grandparent with cancer. FHs of breast cancer, CRC, lung cancer, and prostate cancer were most common among participants with the same diagnosis (odds ratio [OR] for breast cancer, 1.14; P < .001; OR for CRC, 1.08; P = .003; OR for lung cancer, 1.09; P = .008; OR for prostate cancer, 1.14; P < .001). Nearly half of the participants (47%) met national CGC guidelines, and 24.4% of these participants met CGC criteria on the basis of their cancer FH alone. FH was particularly important in determining CGC eligibility for participants with prostate cancer versus breast cancer (OR for FH vs personal history alone, 2.91; 95% confidence interval, 1.94–4.35; P < .001). In clustering analyses, breast and prostate cancer FH–defined clusters were common across all participants. Clustering of CRC and breast cancer FHs was also observed. CONCLUSIONS: ROCS participants reported high rates of cancer FH. The high rate of eligibility for CGC among ROCS participants supports the need for interventions to increase referrals and uptake of CGC among African Americans.

IntroductionThe relationships between morbid obesity, changes in body mass index (BMI) before cancer diagnosis, and lung cancer outcomes by histology (SCLC and NSCLC) have not been well studied.MethodsIndividual level data analysis was performed on 25,430 patients with NSCLC and 2787 patients with SCLC from 16 studies of the International Lung Cancer Consortium evaluating the association between various BMI variables and lung cancer overall survival, reported as adjusted hazard ratios (aHRs) from Cox proportional hazards models and adjusted penalized smoothing spline plots.ResultsOverall survival of NSCLC had putative U-shaped hazard ratio relationships with BMI based on spline plots: being underweight (BMI < 18.5 kg/m2; aHR= 1.56; 95% confidence interval [CI]:1.43-1.70) or morbidly overweight (BMI > 40 kg/m2; aHR= 1.09; 95% CI: 0.95-1.26) at the time of diagnosis was associated with worse stage-specific prognosis, whereas being overweight (25 kg/m2 ≤ BMI < 30 kg/m2; aHR= 0.89; 95% CI: 0.85-0.95) or obese (30 kg/m2 ≤ BMI ≤ 40 kg/m2; aHR= 0.86; 95% CI: 0.82-0.91) was associated with improved survival. Although not significant, a similar pattern was seen with SCLC. Compared with an increased or stable BMI from the period between young adulthood until date of diagnosis, a decreased BMI was associated with worse outcomes in NSCLC (aHR= 1.24; 95% CI: 1.2-1.3) and SCLC patients (aHR=1.26 (95% CI: 1.0-1.6). Decreased BMI was consistently associated with worse outcome, across clinicodemographic subsets.ConclusionsBoth being underweight or morbidly obese at time of diagnosis is associated with lower stage-specific survival in independent assessments of NSCLC and SCLC patients. In addition, a decrease in BMI at lung cancer diagnosis relative to early adulthood is a consistent marker of poor survival.

Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. Methods Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N = 12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. Results Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR = 0.48, 95%CI = 0.30–0.75, p = 0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR = 0.68, 95%CI = 0.61–0.77, p = 4.9 ∗ 10–10). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. Conclusion We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7 years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke., Highlights • CHRNA5 rs16969968 confers risk for earlier lung cancer diagnosis, but quitting produces benefit regardless of genotype. • Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. • Precision prevention allows clinicians to provide personalized health benefits of smoking cessation. This is a report on whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. We determined that quitting smoking is highly beneficial in reducing lung cancer risk levels for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Although CHRNA5 rs16969968 increases risk for earlier lung cancer by 4 years, quitting produces essentially the same benefit for smokers with either high or low genetic risks. Smokers can cut their risk of lung cancer in half and delay its onset by 7 years among those diagnosed. These results are important for smokers to prevent cancer. On average, smokers at all genetic risk levels can largely eliminate their elevated risk for lung cancer by quitting smoking.

Background: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk. Methods: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than −950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than −856 HU on expiratory scan (HUE). Results: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels Conclusion: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer. Impact: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341–7. ©2016 AACR.

Background: African Americans have a higher risk of developing lung cancer than European Americans. Previous studies suggested that certain circulating cytokines were associated with lung cancer. We hypothesized that variations in serum cytokine levels exist between African Americans and European Americans, and increased circulating cytokine levels contribute to lung cancer differently in the two races. Methods: Differences in 10 serum cytokine levels, IL1β, IL4, IL5, IL6, IL8, IL10, IL12, granulocyte macrophage colony-stimulating factor, IFNγ, and TNFα, between 170 African-American and 296 European-American controls from the National Cancer Institute-Maryland (NCI-MD) case–control study were assessed. Associations of the serum cytokine levels with lung cancer were analyzed. Statistically significant results were replicated in the prospective Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and the Wayne State University Karmanos Cancer Institute case–control study. Results: Six cytokines, IL4, IL5, IL8, IL10, IFNγ, and TNFα, were significantly higher among European-American as compared with African-American controls. Elevated IL6 and IL8 levels were associated with lung cancer among both races in all three studies. Elevated IL1β, IL10, and TNFα levels were associated with lung cancer only among African Americans. The association between elevated TNFα levels and lung cancer among European Americans was significant after adjustment for additional factors. Conclusions: Serum cytokine levels vary by race and might contribute to lung cancer differently between African Americans and European Americans. Impact: Future work examining risk prediction models of lung cancer can measure circulating cytokines to accurately characterize risk within racial groups. Cancer Epidemiol Biomarkers Prev; 25(3); 488–97. ©2015 AACR.

Background: Lung cancer continues to cause more deaths than other cancers, with mortality among African Americans higher than among whites. Despite this, research on the psychosocial aspects of lung cancer patients' quality of life lags behind that of other cancer types, such as breast or prostate. The Detroit Research on Cancer Survivors (ROCS) studies follow the experience of cancer survivors, including lung cancer patients, in Detroit, MI. The Detroit ROCS studies include the pilot study of whites and African Americans, and the ongoing study of African Americans only. Methods: Participants in the Detroit ROCS studies complete the Functional Assessment in Cancer Therapy (FACT) instrument to evaluate their health-related quality of life (QOL). FACT scores are derived from subscores evaluating physical, emotional, social, and functional well-being. Higher scores indicate better QOL. In addition, participants are asked to provide basic demographic information, health history, family history of cancer, and exposure history. Data related to their cancer diagnosis and census tract are gathered via the Metropolitan Detroit Cancer Surveillance System. We examined preliminary data collected from 227 (131 African American and 96 white) lung cancer survivors to assess racial differences in self-reported aspects of well-being. We compared descriptive characteristics using Pearson's Chi-square and Wilcoxon rank sum tests. We modeled adjusted mean well-being subscores using a general linear model. Results: The mean age of African American participants was 61.9 (SD=7.6) and the mean age of whites was 62.9 (SD=8.9). Among African American participants, 40.5% were male; of white participants, 45.8% were male. The distributions of age and sex did not differ significantly between groups. African American participants were less likely to have any college education (p=0.0480), and more likely to live in a census tract with at least 20% poverty (p Conclusions: While functional and physical well-being outcomes are similar for African American and white patients after a lung cancer diagnosis, emotional and social well-being outcomes diverge by race. These measures reflect disparities in QOL among lung cancer patients, whose QOL is minimally studied compared to survivors of cancers with lower mortality rates. Future analyses will identify factors influencing this disparity in emotional and social well-being, and describe additional determinants contributing to the QOL of lung cancer survivors. Citation Format: Julia Mantey, Angela Wenzlaff, Jennifer Beebe-Dimmer, Terrance Albrecht, Ann G. Schwartz. Health-related quality of life among Detroit lung cancer survivors: Findings from the Detroit ROCS studies [abstract]. In: Proceedings of the Eleventh AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2018 Nov 2-5; New Orleans, LA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl):Abstract nr B035.

Immunotherapy is a promising advancement in the treatment of non-small-cell lung carcinoma (NSCLC), although much of how lung tumors interact with the immune system in the natural course of disease remains unknown. We investigated the impact of the expression of immune-centric genes and pathways in tumors on patient survival to reveal novel candidates for immunotherapeutic research. Tumor transcriptomes and detailed clinical characteristics were obtained from patients with NSCLC who were participants of either the Inflammation, Health and Lung Epidemiology (INHALE) (discovery, N = 280) or The Cancer Genome Atlas (TCGA) Lung (replication, N = 1026) studies. Expressions of 2253 genes derived from 48 major immune pathways were assessed for association with patient prognosis using a multivariable Cox model and pathway effects were assessed with an in-house implementation of the Gene Set Enrichment Analysis (GSEA) algorithm. Prognosis-guided gene and pathway analysis of immune-centric expression in tumors revealed significant survival enrichments across both cohorts. The ‘Interleukin Signaling’ pathway, containing 430 genes, was found to be statistically and significantly enriched with prognostic signal in both the INHALE (P = 0.008) and TCGA (P = 0.039) datasets. Subsequent leading-edge analysis identified a subset of genes (N = 23) shared between both cohorts, driving the pathway enrichment. Cumulative expression of this leading-edge gene signature was a strong predictor of patient survival [discovery: hazard ratio (HR) = 1.59, P = 3.0 × 10(–8); replication: HR = 1.29, P = 7.4 × 10(–7)]. These data demonstrate the impact of immune-centric expression on patient outcomes in NSCLC. Furthermore, prognostic gene effects were localized to discrete immune pathways, of which Interleukin Signaling had the greatest impact on overall survival and the subset of genes driving these effects have promise for future therapeutic intervention.

Purpose: Identifying novel driver genes and mutations in African American non–small cell lung cancer (NSCLC) cases can inform targeted therapy and improve outcomes for this traditionally underrepresented population. Experimental Design: Tumor DNA, RNA, and germline DNA were collected from African American NSCLC patients who participated in research conducted at the Karmanos Cancer Institute (KCI) in Detroit, Michigan. Known mutations were ascertained through the Sequenom LungCarta panel of 214 mutations in 26 genes, RET/ROS1 fusions, amplification of FGFR1, and expression of ALK. Paired tumor and normal DNA was whole-exome sequenced for a subset of cases without known driver mutations. Results: Of the 193 tumors tested, 77 known driver mutations were identified in 66 patients (34.2%). Sixty-seven of the 127 patients without a known driver mutation were sequenced. In 54 of these patients, 50 nonsynonymous mutations were predicted to have damaging effects among the 26 panel genes, 47 of which are not found in The Cancer Genome Atlas NSCLC white or African American samples. Analyzing the whole-exome sequence data using MutSig2CV identified a total of 88 genes significantly mutated at FDR q < 0.1. Only 5 of these genes were previously reported as oncogenic. Conclusions: These findings suggest that broader mutation profiling including both known and novel driver genes in African Americans with NSCLC will identify additional mutations that may be useful in treatment decision-making.

To identify genetic variation associated with lung cancer risk, we performed a genome-wide association analysis of 685 lung cancer cases that had a family history of two or more first or second degree relatives compared with 744 controls without lung cancer that were genotyped on an Illumina Human OmniExpressExome-8v1 array. To ensure robust results, we further evaluated these findings using data from six additional studies that were assembled through the Transdisciplinary Research on Cancer of the Lung Consortium comprising 1993 familial cases and 33 690 controls. We performed a meta-analysis after imputation of all variants using the 1000 Genomes Project Phase 1 (version 3 release date September 2013). Analyses were conducted for 9 327 222 SNPs integrating data from the two sources. A novel variant on chromosome 4p15.31 near the LCORL gene and an imputed rare variant intergenic between CDKN2A and IFNA8 on chromosome 9p21.3 were identified at a genome-wide level of significance for squamous cell carcinomas. Additionally, associations of CHRNA3 and CHRNA5 on chromosome 15q25.1 in sporadic lung cancer were confirmed at a genome-wide level of significance in familial lung cancer. Previously identified variants in or near CHRNA2, BRCA2, CYP2A6 for overall lung cancer, TERT, SECISPB2L and RTEL1 for adenocarcinoma and RAD52 and MHC for squamous carcinoma were significantly associated with lung cancer.

Introduction Lung cancer is a leading cause of cancer-related death worldwide. Racial disparities in lung cancer survival exist between blacks and whites, yet they are limited by categorical definitions of race. We sought to examine the impact of African ancestry on overall survival among blacks and whites with NSCLC cases. Methods Incident cases of NSCLC in blacks and whites from the prospective Southern Community Cohort Study (N = 425) were identified through linkage with state cancer registries in 12 southern states. Vital status was determined by linkage with the National Death Index and Social Security Administration. We evaluated the impact of African ancestry (as estimated by using genome-wide ancestry-informative markers) on overall survival by calculating the time-dependent area under the curve (AUC) for Cox proportional hazards models, adjusting for relevant covariates such as stage and treatment. We replicated our findings in an independent population of NSCLC cases in blacks. Results Global African ancestry was not significantly associated with overall survival among NSCLC cases. There was no change in model performance when Cox proportional hazards models with and without African ancestry were compared (AUC = 0.79 for each model). Removal of stage and treatment reduced the average time-dependent AUC from 0.79 to 0.65. Similar findings were observed in our replication study. Conclusions Stage and treatment are more important predictors of survival than African ancestry is. These findings suggest that racial disparities in lung cancer survival may disappear with similar early detection efforts for blacks and whites.

Introduction: Lung cancer is the leading cause of cancer-related deaths in the US. The reasons for higher incidence and poorer sur- vival rates among black compared with white lung cancer patients have not been defined. We hypothesized that differential incidence of somatic cancer gene mutations may be a contributing factor. Previous genomic studies of non-small cell lung cancer (NSCLC) have not adequately represented black patients. Methods: A matrix-assisted laser desorption/ionization and time-of- flight mass spectrometry approach was used to analyze tumor DNA for 214 coding mutations in 26 cancer genes previously identified in NSCLC. The samples included NSCLC from 335 white patients and 137 black patients. For 299 of these, normal matched DNA was available and analyzed. Results: Epidermal growth factor receptor (EGFR) exon 19 deletions were only detected in women cases, with increased odds for black women compared with white women (odds ratio = 3.914, 95% confidence inter - val: 1.014-15.099, p = 0.048). Beyond race, variations in mutation fre- quencies were seen by histology. DDR2 alterations, previously described as somatic mutations, were identified as constitutional variants. Conclusions: This study is among the largest comparing somatic mutations in black and white patients. The results point to the molec- ular diversity of NSCLC and raise new questions as to the impor- tance of inherited alleles. Genomic tumor testing will benefit both populations, although the mutation spectrum appears to vary by sex, race, and histology.

Lung cancer has a familial component which suggests a genetic contribution to its etiology. Given the strong evidence linking smoking with lung cancer, we studied miRNA-related loci in genes associated with smoking behavior. CHRNA, CHRNB gene families, CYP2A6, and DRD1 (dopamine receptor D1) were mined for SNPs that fell within the seed region of miRNA binding sites and then tested for associations with risk in a three-stage validation approach. A 3′UTR (untranslated region) SNP in DRD1 was associated with a lower risk of lung cancer among individuals exposed to secondhand smoke during childhood [OR, 0.69; 95% confidence interval (CI), 0.60–0.79; P < 0.0001]. This relationship was evident in both ever (OR, 0.74; 95% CI, 0.62–0.88; P = 0.001) and never smokers (OR, 0.61; 95% CI, 0.47–0.79; P < 0.0001), European American (OR, 0.65; 95% CI, 0.53–0.80; P < 0.0001), and African American (OR, 0.73; 95% CI, 0.62–0.88; P = 0.001) populations. Although much remains undefined about the long-term risks associated with exposure to secondhand smoke and heterogeneity between individuals in regard to their susceptibility to the effects of secondhand smoke, our data show an interaction between an SNP in the 3′UTR of DRD1 and exposure to secondhand smoke during childhood. Further work is needed to explore the mechanistic underpinnings of this SNP and the nature of the interaction between DRD1 and exposure to secondhand smoke during childhood. Cancer Prev Res; 7(12); 1210–8. ©2014 AACR.

Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases. Methods: Incident non–small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication. Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54–0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71–0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33–0.66). Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene–environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival. Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288–95. ©2017 AACR.

Introduction: Although lung cancer is the leading cause of cancer death in women, few studies have investigated the hormonal influence on survival after a lung cancer diagnosis and results have been inconsistent. We evaluated the role of reproductive and hormonal factors in predicting overall survival in women with non–small-cell lung cancer (NSCLC). Methods: Population-based lung cancer cases diagnosed between November 1, 2001 and October 31, 2005 were identified through the Metropolitan Detroit Surveillance, Epidemiology, and End Results Registry. Interview and follow-up data were collected for 485 women. Cox proportional hazard regression models were used to determine hazard ratios (HRs) for death after an NSCLC diagnosis associated with reproductive and hormonal variables. Results: Use of hormone therapy (HT) was associated with improved survival (HR, 0.69; 95% confidence interval, 0.54–0.89), adjusting for stage, surgery, radiation, education level, pack-years of smoking, age at diagnosis, race, and a multiplicative interaction between stage and radiation. No other reproductive or hormonal factor was associated with survival after an NSCLC diagnosis. Increased duration of HT use before the lung cancer diagnosis (132 months or longer) was associated with improved survival (HR, 0.54; 95% confidence interval, 0.37–0.78), and this finding remained significant in women taking either estrogen alone or progesterone plus estrogen, never smokers, and smokers. Conclusion: These findings suggest that HT use, in particular use of estrogen plus progesterone, and long-term HT use are associated with improved survival of NSCLC.

It is not clear whether alcohol consumption is associated with lung cancer risk. The relationship is likely confounded by smoking, complicating the interpretation of previous studies. We examined the association of alcohol consumption and lung cancer risk in a large pooled international sample, minimizing potential confounding of tobacco consumption by restricting analyses to never smokers. Our study included 22 case-control and cohort studies with a total of 2548 never-smoking lung cancer patients and 9362 never-smoking controls from North America, Europe and Asia within the International Lung Cancer Consortium (ILCCO) and SYNERGY Consortium. Alcohol consumption was categorized into amounts consumed (grams per day) and also modelled as a continuous variable using restricted cubic splines for potential non-linearity. Analyses by histologic sub-type were included. Associations by type of alcohol consumed (wine, beer and liquor) were also investigated. Alcohol consumption was inversely associated with lung cancer risk with evidence most strongly supporting lower risk for light and moderate drinkers relative to non-drinkers (>0-4.9 g per day: OR = 0.80, 95% CI = 0.70-0.90; 5-9.9 g per day: OR = 0.82, 95% CI = 0.69-0.99; 10-19.9 g per day: OR = 0.79, 95% CI = 0.65-0.96). Inverse associations were found for consumption of wine and liquor, but not beer. The results indicate that alcohol consumption is inversely associated with lung cancer risk, particularly among subjects with low to moderate consumption levels, and among wine and liquor drinkers, but not beer drinkers. Although our results should have no relevant bias from the confounding effect of smoking we cannot preclude that confounding by other factors contributed to the observed associations. Confounding in relation to the non-drinker reference category may be of particular importance.

IntroductionBlack/white disparities in lung cancer incidence and mortality mandate an evaluation of underlying biological differences. We have previously shown higher risks of lung cancer associated with prior emphysema in African American compared with white patients with lung cancer.MethodsWe therefore evaluated a panel of 1440 inflammatory gene variants in a two-phase analysis (discovery and replication), added top genome-wide association studies (GWAS) lung cancer hits from white populations, and 28 single-nucleotide polymorphisms (SNPs) from a published gene panel. The discovery set (477 self-designated African Americans cases, 366 controls matched on age, ethnicity, and gender) were from Houston, Texas. The external replication set (330 cases and 342 controls) was from the EXHALE study at Wayne State University.ResultsIn discovery, 154 inflammation SNPs were significant (p < 0.05) on univariate analysis, as was one of the gene panel SNPs (rs308738 in REV1, p = 0.0013), and three GWAS hits, rs16969968 p = 0.0014 and rs10519203 p = 0.0003 in the 15q locus and rs2736100, in the HTERT locus, p = 0.0002. One inflammation SNP, rs950286, was successfully replicated with a concordant odds ratio of 1.46 (1.14–1.87) in discovery, 1.37 (1.05–1.77) in replication, and a combined odds ratio of 1.40 (1.17–1.68). This SNP is intergenic between IRF4 and EXOC2 genes. We also constructed and validated epidemiologic and extended risk prediction models. The area under the curve (AUC) for the epidemiologic discovery model was 0.77 and 0.80 for the extended model. For the combined datasets, the AUC values were 0.75 and 0.76, respectively.ConclusionsAs has been reported for other cancer sites and populations, incorporating top genetic hits into risk prediction models, provides little improvement in model performance and no clinical relevance.

Background: Genome-wide association studies of European and East Asian populations have identified lung cancer susceptibility loci on chromosomes 5p15.33, 6p22.1-p21.31, and 15q25.1. We investigated whether these regions contain lung cancer susceptibly loci in African-Americans and refined previous association signals by using the reduced linkage disequilibrium observed in African-Americans. Methods: 1,308 African-American cases and 1,241 African-American controls from 3 centers were genotyped for 760 single-nucleotide polymorphisms (SNP) spanning 3 regions, and additional SNP imputation was carried out. Associations between polymorphisms and lung cancer risk were estimated using logistic regression, stratified by tumor histology where appropriate. Results: The strongest associations were observed on 15q25.1 in/near CHRNA5, including a missense substitution [rs16969968: OR, 1.57; 95% confidence interval (CI), 1.25–1.97; P, 1.1 × 10−4) and variants in the 5′-UTR. Associations on 6p22.1-p21.31 were histology specific and included a missense variant in BAT2 associated with squamous cell carcinoma (rs2736158: OR, 0.64; 95% CI, 0.48–0.85; P, 1.82 × 10−3). Associations on 5p15.33 were detected near TERT, the strongest of which was rs2735940 (OR, 0.82; 95% CI, 0.73–0.93; P, 1.1 × 10−3). This association was stronger among cases with adenocarcinoma (OR, 0.75; 95% CI, 0.65–0.86; P, 8.1 × 10−5). Conclusions: Polymorphisms in 5p15.33, 6p22.1-p21.31, and 15q25.1 are associated with lung cancer in African-Americans. Variants on 5p15.33 are stronger risk factors for adenocarcinoma and variants on 6p21.33 associated only with squamous cell carcinoma. Impact: Results implicate the BAT2, TERT, and CHRNA5 genes in the pathogenesis of specific lung cancer histologies. Cancer Epidemiol Biomarkers Prev; 22(2); 251–60. ©2012 AACR.

// Kyle M. Walsh 1 †, Christopher I. Amos 2 † * , Angela S. Wenzlaff 3 , Ivan P. Gorlov 4 , Jennette D. Sison 5 , Xifeng Wu 6 , Margaret R. Spitz 7 , Helen M. Hansen 5 , Emily Y. Lu 2 , Chongjuan Wei 6 , Huifeng Zhang 2 , Wei Chen 2 , Stacy M. Lloyd 8 , Marsha L. Frazier 6 , Paige M. Bracci 1 , Michael F. Seldin 9 , Margaret R. Wrensch 1,5 , Ann G. Schwartz 3* , John K. Wiencke 1,5* 1 Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA 2 Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 3 Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 4 Department of Genitourinary Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 5 Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 6 Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, TX 7 Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 8 Department of Health Disparities Research, University of Texas M.D. Anderson Cancer Center, Houston, TX 9 Department of Biochemistry and Molecular Medicine, University of California, Davis † denotes equal contribution * CIA, AGS and JKW co-directed this research Correspondence: John K. Wiencke, email: // Keywords : Lung cancer, nicotine dependence, African-Americans, genetic association, smoking Received : November 13, 2012, Accepted : November 14, 2012, Published : November 16, 2012 Abstract Studies in European and East Asian populations have identified lung cancer susceptibility loci in nicotinic acetylcholine receptor (nAChR) genes on chromosome 15q25.1 which also appear to influence smoking behaviors. We sought to determine if genetic variation in nAChR genes influences lung cancer susceptibly in African-Americans, and evaluated the association of these cancer susceptibility loci with smoking behavior. A total of 1308 African-Americans with lung cancer and 1241 African-American controls from three centers were genotyped for 378 single nucleotide polymorphisms (SNPs) spanning the sixteen human nAChR genes. Associations between SNPs and the risk of lung cancer were estimated using logistic regression, adjusted for relevant covariates. Seven SNPs in three nAChR genes were significantly associated with lung cancer at a strict Bonferroni-corrected level, including a novel association on chromosome 2 near the promoter of CHRNA1 (rs3755486: OR = 1.40, 95% CI = 1.18-1.67, P = 1.0 x 10 -4 ). Association analysis of an additional 305 imputed SNPs on 2q31.1 supported this association. Publicly available expression data demonstrated that the rs3755486 risk allele correlates with increased CHRNA1 gene expression. Additional SNP associations were observed on 15q25.1 in genes previously associated with lung cancer, including a missense variant in CHRNA5 (rs16969968: OR = 1.60, 95% CI = 1.27-2.01, P = 5.9 x 10 -5 ). Risk alleles on 15q25.1 also correlated with an increased number of cigarettes smoked per day among the controls. These findings identify a novel lung cancer risk locus on 2q31.1 which correlates with CHRNA1 expression and replicate previous associations on 15q25.1 in African-Americans.